A growing appreciation and understanding of the link between viral infections and cancer has significantly influenced cancer treatment and prevention by offering the possibility of new drug/vaccine targets;however, efforts to further advance viral cancer research have been hampered by the lack of 1) sophisticated high throughput molecular virology technologies and 2) accessible comprehensive and well characterized cancer tissues. To address this issue, the NCI "Identifying Potential Viral Signatures in Large Scale Studies of Germline and Somatic Changes in Cancer Genomes Pilot Program" includes calls for the development of targeted high throughput viral screening using selected tumors that have been characterized for genomic alterations. As such, the overall objective of this proposal is to apply an innovative, streamlined approach to facilitate the discovery of previously unidentified viral associations in the well-characterized specimens of The Cancer Genome Atlas (TCGA) project. Our pilot effort will utilize highly innovative techniques to identify new and novel viral signatures, with the ultimate goal of forming the basis for future studies to investigate the link between viral infection and all human malignancies. Accordingly, the specific aims of this proposal are: 1) Using consensus and degenerate primer PCR, we will search for retroviruses in available TCGA specimens. 2) Using a pan-viral microarray platform, which has the ability to screen for known and unknown viruses from all recognized viral families, we will explore the TCGA specimens for viral sequences. 3) Using sequence independent sequencing methods and metagenomic analysis, we will explore the possibility that highly divergent viruses and viruses from previously unknown viral families may exist within TCGA specimens. Overall, these three distinct but complimentary approaches will further our understanding of viral-cancer associations paving the way for the potential development of new therapeutics for cancer treatment and prevention. PUBLIC HEALTH RELEVANCE: The research proposed here utilizes a world class viral discovery laboratory network assembled by Global Viral Forecasting Inc, to, for the first time systematically apply novel molecular techniques to the discovery of viruses in human malignancies. By utilizing a comprehensive strategy toward viral discovery along with the high quality specimens from The Cancer Genome Atlas (TCGA) project, the proposed research program sets to establish a framework for large-scale systematic collaboration with NCI to discover the full range of viruses associated with human malignancy.